Ribomustin 25 mg/100 mg Solution

Ribomustinu2122 (bendamustine hydrochloride) powder for reconstitution is indicated for:

• First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
• First-line treatment of indolent CD 20 positive non-Hodgkinu2019s lymphoma in combination with rituximab.
• Indolent non-Hodgkinu2019s lymphomas as monotherapy in patients, who have progressed during or within 6 months following treatment with rituximab or a rituximab containing regimen.
• Front line treatment of multiple myeloma (Durie-Salmon stage II with progress or stage III) in combination with prednisone for patients older than 65 years who are not eligible for autologous stem cell transplantation and who have clinical neuropathy at time of diagnosis precluding the use of thalidomide or bortezomib containing treatment.

4.2.1 Posology

For intravenous infusion over 30 to 60 minutes. Infusion must be administered under the supervision of a medical practitioner qualified and experienced in the use of chemotherapeutic agents. Poor bone marrow function is related to increased chemotherapy-induced haematological toxicity. Treatment should not be started if leukocyte and/or platelet values dropped to < 3 x 109/u2113 or < 75 x 109/u2113, respectively (see section 4.3).

Monotherapy for chronic lymphocytic leukaemia

100 mg/m2 body surface area RIBOMUSTIN on days 1 and 2; every 4 weeks.

Combination treatment for first-line indolent non-Hodgkinu2019s lymphoma

90 mg/m2 body surface area RIBOMUSTIN on days 1 and 2 in combination with 375 mg/m2 body surface area rituximab as a slow i.v. infusion on day 1; every 4 weeks.

Monotherapy for indolent non-Hodgkinu2019s lymphomas refractory to rituximab

120 mg/m2 body surface area RIBOMUSTIN on days 1 and 2; every 3 weeks.

Multiple Myeloma

120-150 mg/m2 body surface area RIBOMUSTIN on days 1 and 2, 60 mg/m2 body surface area prednisone i.v. or orally on days 1 to 4; every 4 weeks. Treatment should be terminated or delayed if leukocyte and/or platelet values dropped to u2264 3 x 109/u2113 or u2264 75 x 109/u2113, respectively. Treatment can be continued after leukocyte values have increased to > 4 x 109/u2113 and platelet values to > 100 x 109/u2113. The leukocyte and platelet Nadir is reached, after 14 - 20 days with regeneration after 3 - 5 weeks. During therapy free intervals strict monitoring of the blood count is recommended (see section 4.4.). In case of non-haematological toxicity dose reductions have to be based on the worst CTC grades in the preceding cycle. A 50 % dose reduction is recommended in case of CTC grade 3 toxicity. An interruption of treatment is recommended in case of CTC grade 4 toxicity. If a patient requires a dose modification the individually calculated reduced dose must be given on day 1 and 2 of the respective treatment cycle. For administration, see Section 4.2.4 Method of Administration and for preparation, see section 6.6.

4.2.2 Special Populations

Elderly patients

There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).

Hepatic impairment

On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment [serum bilirubin < 20,52 u03bcmol/u2113 (< 1,2 mg/dl)]. A 30 % dose reduction is recommended in patients with moderate hepatic impairment (serum bilirubin [34,2 u03bcmol/u2113 u2013 51,3 u03bcmol/u2113 (2 u2013 3,0 mg/dl)].

Renal impairment

On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with a creatinine clearance of > 10 ml/min. Experience in patients with severe renal impairment is limited.

4.2.3 Paediatric Population

There is no experience in children and adolescents with RIBOMUSTIN.

4.2.4 Method of Administration

For single use only. The clear, colourless solution is administered by intravenous infusion over 30 - 60 min. See section 6.6 for instructions for reconstitution. Any unused product or waste material should be disposed of in accordance with local requirements (see section 6.6).

• Hypersensitivity to bendamustine or to any of the excipients in RIBOMUSTIN (see section 6.1)
• Pregnancy and lactation (see section 4.6)
• Severe hepatic impairment [serum bilirubin > 51,3 u03bcmol/u2113 (3 mg/dl)]
• Jaundice
• Severe bone marrow suppression and severe blood count alterations (leukocyte and/or platelet values dropped to < 3 x 109/u2113 or < 75 x 109/u2113, respectively)
• Major surgery less than 30 days before start of treatment
• Infections, especially involving leukocytopenia
• Yellow fever vaccination or any other live (attenuated) vaccination
• Congenital QT prolongation
• Concomitant medicines causing QT prolongation.

Myelosuppression

Patients treated with RIBOMUSTIN experience myelosuppression. Treatment-related myelosuppression, leukocytes, platelets, haemoglobin, and neutrophils must be monitored at least weekly. Prior to the initiation of the next cycle of therapy, the following parameters are recommended: Leukocyte and/or platelet values > 4 x 109/u2113 or > 100 x 109/u2113, respectively.

Infections

Cases of tuberculosis have been less frequently reported compared to other infections. Latent or dormant tuberculosis may become active. The presence of tuberculosis should be excluded before treatment with RIBOMUSTIN is commenced. Serious and fatal infections have occurred with RIBOMUSTIN, including tuberculosis, bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), varicella zoster virus (VZV) and cytomegalovirus (CMV). Treatment with RIBOMUSTIN may cause prolonged lymphocytopenia (< 600/u03bcl) and low CD4-positive T-cell (T-helper cell) counts (< 200 /u03bcl) for at least 7 u2013 9 months after the completion of treatment. Infection has been associated with hospitalisation, septic shock, and death.

Patients with lymphopenia and low CD4-positive T-cell count following treatment with RIBOMUSTIN are more susceptible to opportunistic infections including tuberculosis. Patients with myelosuppression following RIBOMUSTIN treatment should be advised to contact a medical practitioner if they have symptoms or signs of infection, including fever or respiratory symptoms. Therefore, patients should be monitored for respiratory signs and symptoms throughout treatment. Patients should be advised to report new signs of infection, including fever or respiratory symptoms promptly. Discontinuation of RIBOMUSTIN should be considered if there are signs of (opportunistic) infections.

Cytomegalovirus and herpes virus reactivation have been reported and may occur.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received RIBOMUSTIN. Some cases resulted in acute hepatic failure or fatal outcome. Patients should be tested for HBV infection before initiating treatment with RIBOMUSTIN. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B tests (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with RIBOMUSTIN should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see Side Effects).

Skin reactions

A number of skin reactions have been reported which include rash, severe cutaneous reactions, and bullous exanthema. Cases of Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported with the use of RIBOMUSTIN. Some of these events occurred when RIBOMUSTIN was given in combination with other anticancer agents. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use of RIBOMUSTIN in combination with rituximab. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, RIBOMUSTIN should be withheld or discontinued. For severe skin reactions where a relationship to RIBOMUSTIN is suspected, treatment should be discontinued.

Cardiac disorders

Fatal cases of myocardial infarction and cardiac failure have been reported with RIBOMUSTIN treatment. Patients with concurrent or history of cardiac disease should be observed closely. QTcf was prolonged by more than 30 msecs in 4 of 9 patients studied. During treatment with RIBOMUSTIN the concentration of potassium in the blood of patients with cardiac disorders must be closely monitored. When serum potassium levels are < 3,5 mEq/u2113 (3,5 mmol/u2113), an ECG recording must be performed, and a potassium supplement must be given.

Nausea, vomiting

An antiemetic should be given for the symptomatic treatment of nausea and vomiting.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) associated with RIBOMUSTIN treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of RIBOMUSTIN and, without intervention, may lead to acute renal failure and death. Preventive measures such as adequate hydration close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of hypouricaemic medicines (allopurinol and rasburicase) should be considered prior to and during therapy with RIBOMUSTIN. There have been cases of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis reported when RIBOMUSTIN and allopurinol are administered concomitantly.

Anaphylaxis

Infusion reactions to RIBOMUSTIN have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. Severe anaphylactic and anaphylactoid reactions have occurred. Patients must be questioned about symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids must be considered in subsequent cycles in patients who have previously experienced infusion reactions. In patients who experienced Grade 3 or worse allergic-type reactions, RIBOMUSTIN should be discontinued.

Contraception

RIBOMUSTIN is teratogenic and mutagenic (see section 4.3 and section 4.6).

Extravasation

An extravasal injection should be stopped immediately. The needle should be removed after a short aspiration. Thereafter the affected area of tissue should be cooled. The arm should be elevated. Additional treatments like the use of corticosteroids are not of clear benefit. There have been reports of necrosis after accidental extra-vascular administration and tumour lysis syndrome, and anaphylaxis.

The risk of myelodysplastic syndrome and acute myeloid leukaemias is increased in patients treated with alkylating agents (including bendamustine). The secondary malignancy may develop several years after chemotherapy has been discontinued.

No in-vivo interaction studies have been performed. When RIBOMUSTIN is combined with myelosuppressive agents, the effect of RIBOMUSTIN and/or the co-administered medicinal products on the bone marrow may be potentiated. Any treatment reducing the patientu2019s performance status or impairing bone marrow function can increase the toxicity of RIBOMUSTIN. Combination of RIBOMUSTIN with ciclosporin or tacrolimus may result in excessive immunosuppression with risk of lymphoproliferation. RIBOMUSTIN can reduce antibody formation following live-virus vaccination and increase the risk of infection which may lead to fatal outcome. This risk is increased in subjects who are already immunosuppressed by their underlying disease (see section 4.3). RIBOMUSTIN metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine exist.

RIBOMUSTIN is contraindicated in pregnancy and lactation (see section 4.3). Women of childbearing potential/Contraception in males and females

RIBOMUSTIN therapy may cause teratogenicity and other reproductive adverse events due to its genotoxic nature. In males, RIBOMUSTIN may cause DNA damage in the sperm, potentially resulting in adverse events in the embryo or foetus of a female sexual partner. In females, RIBOMUSTIN may directly affect the embryo or foetus; or may cause DNA damage in the oocytes. To minimise the risk of drug-induced heritable DNA damage and to ensure that genomic integrity of gametes at the time of conception is maintained, women of childbearing potential, that is female patients using RIBOMUSTIN and female sexual partners of male patients receiving this product are generally advised to use highly effective contraception during treatment and for an adequate period, following the end of treatment. Male patients should be advised to use highly effective contraception while receiving treatment with RIBOMUSTIN, until the end of relevant systemic exposure to this product, including its potential genotoxic metabolites (i.e., five half-lives after the last dose) plus 90 days (i.e., 60u201375 days for sperm production plus 10 u201314 days for the transport to the epididymis). Male patients should not father a child during and up to 3 months after treatment. They should seek advice about sperm conservation prior to treatment with RIBOMUSTIN because of possible irreversible infertility. Women of childbearing potential, that is female patients using RIBOMUSTIN and female sexual partners of male patients receiving this product, should be advised to use highly effective contraception until the end of relevant systemic exposure to RIBOMUSTIN, including its potential genotoxic metabolites (i.e., five half-lives after the last dose) plus 6 months (which covers the growth and maturation phase of folliculogenesis). It is therefore suggested that contraception continue for at least 6 months after treatment.

Pregnancy

Women should not become pregnant during treatment.

Breastfeeding

It is not known whether RIBOMUSTIN passes into breast milk. Treatment with RIBOMUSTIN is contraindicated during breastfeeding (see section 4.3). Mothers on RIBOMUSTIN must not breastfeed their babies.

Fertility

In nonclinical studies, RIBOMUSTIN was embryo-/foetolethal, teratogenic, mutagenic, and genotoxic.

RIBOMUSTIN influences the ability to drive and use machines. Ataxia, peripheral neuropathy, and somnolence have been reported during treatment with RIBOMUSTIN (see section 4.8). Patients should be instructed to avoid potentially hazardous tasks such as driving and using machines while on treatment with RIBOMUSTIN.

a. Summary of the safety profile

The most common side effects with RIBOMUSTIN are haematological adverse reactions (leukopenia, thrombocytopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).

b. Tabulated summary of adverse reactions

The frequency of side effects is classified as very common ( u2265 1/10), common ( u2265 1/100, < 1/10), uncommon ( u2265 1/1 000, < 1/100), rare ( u2265 1/10 000, < 1/1 000) or very rare (< 1/10 000).

Infections and infestations

Very common: Infection (not otherwise specified), including opportunistic infections (e.g. Herpes zoster, cytomegalovirus, hepatitis B)

Uncommon: Pneumocystis jirovecii pneumonia

Rare: Septicaemia

Very rare: Primary atypical pneumonia, tuberculosis

Neoplasms benign, malignant, and unspecified (including cysts and polyps)

Common: Tumour lysis syndrome

Uncommon: Myelodysplastic syndrome, acute myeloid leukaemia

Blood and lymphatic system disorders

Very common: Leukopenia (not otherwise specified), thrombocytopenia, lymphopenia

Common: Haemorrhage, anaemia, neutropenia

Uncommon: Pancytopenia

Rare: Bone marrow failure

Very rare: Haemolysis

Immune system disorders

Common: Hypersensitivity (not otherwise specified)

Rare: Anaphylactic reaction, anaphylactoid reaction

Very rare: Anaphylactic shock

Nervous system disorders

Very common: Headache

Common: Insomnia, dizziness

Rare: Somnolence, aphonia

Very rare: Dysgeusia, paraesthesia, peripheral sensory neuropathy, anticholinergic syndrome, neurological disorders, ataxia, encephalitis

Cardiac disorders

Common: Cardiac dysfunction, such as palpitations, angina pectoris; dysrhythmia, QT prolongation

Uncommon: Pericardial effusion, myocardial infarction, cardiac failure

Very rare: Tachycardia

Not known (cannot be estimated from the available data): Atrial fibrillation

Vascular disorders

Common: Hypotension, hypertension

Rare: Acute circulatory failure

Very rare: Phlebitis

Respiratory, thoracic and mediastinal disorders

Common: Pulmonary dysfunction

Very rare: Pulmonary fibrosis

Not known (cannot be estimated from the available data): Pneumonitis, pulmonary alveolar haemorrhage

Gastrointestinal disorders

Very common: Nausea, vomiting

Common: Diarrhoea, constipation, stomatitis

Very rare: Haemorrhagic oesophagitis, gastrointestinal haemorrhage

Hepatobiliary disorders

Not known (cannot be estimated from the available data): Hepatic failure

Skin and subcutaneous tissue disorders

Common: Alopecia, skin disorders (not otherwise specified)

Rare: Erythema, dermatitis, pruritus, maculo-papular rash, hyperhidrosis

Not known (cannot be estimated from the available data): Stevens-Johnson syndrome, Toxic Epidermal Necrolysis

Drug reaction with eosinophilia and systemic symptoms (DRESS)*

* combination therapy with rituximab

Renal and urinary disorders

Not known (cannot be estimated from the available data): Renal failure. Risk of nephrogenic diabetes insipidus

Reproductive system and breast disorders

Common: Amenorrhoea

Very rare: Infertility

General disorders and administration site conditions

Very common: Mucosal inflammation, fatigue, pyrexia

Common: Pain, chills, dehydration, anorexia

Very rare: Multi-organ failure

Investigations

Very common: Decreased haemoglobin, increased creatinine, increased urea

Common: Increased AST, increased ALT, increased alkaline phosphatase, increased bilirubin, hypokalaemia.

There is no specific antidote. Bone marrow transplantation and transfusions (platelets, concentrated erythrocytes) may be made, or haematological growth factors may be given as effective countermeasures to control haematological side effects. RIBOMUSTIN and its metabolites are dialysable to a small extent.